EP0005250B1 - Hydroxypropyl-imidazoles, procédé pour leur préparation et médicaments les contenant - Google Patents

Hydroxypropyl-imidazoles, procédé pour leur préparation et médicaments les contenant Download PDF

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Publication number
EP0005250B1
EP0005250B1 EP79101288A EP79101288A EP0005250B1 EP 0005250 B1 EP0005250 B1 EP 0005250B1 EP 79101288 A EP79101288 A EP 79101288A EP 79101288 A EP79101288 A EP 79101288A EP 0005250 B1 EP0005250 B1 EP 0005250B1
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EP
European Patent Office
Prior art keywords
formula
methyl
acid
imidazol
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP79101288A
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German (de)
English (en)
Other versions
EP0005250A2 (fr
EP0005250A3 (en
Inventor
Erik Regel
Karl Heinz Prof. Dr. Büchel
Ingo Dr. Haller
Manfred Dr. Plempel
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Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE19782820489 external-priority patent/DE2820489A1/de
Priority claimed from DE19782832677 external-priority patent/DE2832677A1/de
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0005250A2 publication Critical patent/EP0005250A2/fr
Publication of EP0005250A3 publication Critical patent/EP0005250A3/xx
Application granted granted Critical
Publication of EP0005250B1 publication Critical patent/EP0005250B1/fr
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to new hydroxypropylimidazoles, several processes for their preparation and their use as medicaments, in particular as antifungals.
  • Antifungal substances have also become known from DE-AS 2623129. However, their antifungal effects, especially against Candida albicans, Torulapsis glabrata, Trichophyton mentagr. and Microsporum camis, not from.
  • hydroxypropylimidazoles obtainable according to the invention can be converted into the salts by reaction with acids.
  • the hydroxypropylimidazoles according to the invention in addition to good antifungal activity in vitro, show better, therapeutically usable in vivo activity against Candida than the 1- [2,4-dichloro- ⁇ - (2, 4-dichlorobenzyloxy) phenethyl] imidazole nitrate, which is a recognized good agent with the same direction of action.
  • the active compounds according to the invention thus represent a valuable addition to the pharmaceutical industry.
  • R represents phenyl, which is optionally mono- or disubstituted by chlorine, fluorine or methyl, naphthyl or tetrahydronaphthyl
  • R 1 is phenyl which is optionally mono- or disubstituted by chlorine, bromine, fluorine, methyl, ethyl, isopropyl or isopropynyl, cyclopentyl or cyclohexyl
  • R 2 is hydrogen, or R 1 and R 2 together are in the ortho position to one another for a tri, tetra or pentamethylene bridge.
  • Formula (11) provides a general definition of the imidazolylmethylphenyl ketones to be used as starting materials for process variant (a).
  • R I and R 2 preferably represent the radicals which have already been mentioned as preferred in the compounds of the formula (I).
  • Formula (111) provides a general definition of the Grignard compounds to be used as starting materials for process variant (a).
  • R preferably represents the radicals which have already been mentioned as preferred for the compounds of the formula (I).
  • Formula (IV) provides a general definition of the 1-halopropan-2-ols to be used as starting materials for process variant (b).
  • R, R 1 and R 2 preferably represent the radicals which have already been mentioned as preferred for the compounds of the formula (I).
  • the 1-halopropan-2-ols of the formula (IV) are not yet known. However, they can be prepared in a generally customary and known manner by reacting ketones of the formula (VI) with Grignard compounds of the formula (111) in accordance with process variant (a) (see also the details in DE-OS 2 623 129 as well as the manufacturing examples).
  • All solvents customary for a Grignard reaction are suitable as diluents for the reaction according to the invention according to process (a). These preferably include ethers such as diethyl ether or tetrahydrofuran and mixtures with other organic solvents, such as. B. Benzene.
  • reaction temperatures can be varied within a wide range in process (a). Generally one works between about 20 to about 120 ° C, preferably between about 30 to about 80 ° C.
  • Inert organic solvents are preferred diluents for the reaction according to the invention in process (b).
  • These preferably include ketones, such as diethyl ketone, in particular acetone and methyl ethyl ketone; Nitriles, such as propionitrile, especially acetonitrile; Alcohols, such as ethanol or isopropanol; Ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene, toluene and dichlorobenzene; Formamides, such as especially dimethylformamide; and halogenated hydrocarbons such as methylene chloride, carbon tetrachloride or chloroform.
  • ketones such as diethyl ketone, in particular acetone and methyl ethyl ketone
  • Nitriles such as propionitrile, especially acetonitrile
  • Alcohols such as ethanol or isopropanol
  • Ethers such as t
  • process (b) according to the invention is carried out in the presence of an acid binder, it is possible to add all of the customarily used inorganic or organic acid binders, such as alkali carbonate, for example sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or such as lower tertiary alkylamines, cycloalkylamines or aralkylamines, for example triethylamine, N, N-dimethylcyclohexylamine, dicyclohexylmethylamine, N, N-dimethylbenzylamine, further pyridine and diazabicyclooctane. An excess of imidazole is preferably used.
  • alkali carbonate for example sodium carbonate, potassium carbonate and sodium hydrogen carbonate
  • lower tertiary alkylamines, cycloalkylamines or aralkylamines for example triethylamine, N, N-dimethylcyclohexylamine, dicyclohexylmethyl
  • reaction temperatures can be varied within a wide range in process (b). Generally one works between about 30 to about 200 ° C, preferably at the boiling point of the solvent.
  • 1 to 2.5 mol of midazole and 1 to 2.5 mol of acid binder are preferably employed per mol of the compounds of the formula (IV).
  • 1 to 1.5 moles of alkali salt are preferably used per mole of the compound of formula (IV).
  • the solvent is distilled off, the residue is washed with water directly or after being taken up in an organic solvent, the organic phase is optionally dried over sodium sulfate and the solvent is removed in vacuo. The residue is optionally purified by distillation, recrystallization or by chromatography.
  • All physiologically compatible acids are suitable for the preparation of acid addition salts of the compounds of the formula (I).
  • These preferably include the hydrohalic acids, such as. B. the hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as. B. acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and sulfonic acids, such as. B. p-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.
  • the hydrohalic acids such as. B. the hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as. B. acetic acid,
  • the salts of the compounds of formula (I) can be easily prepared by conventional salt formation methods, e.g. B. by dissolving a compound of formula (I) in a suitable inert solvent and adding the acid, e.g. As hydrochloric acid can be obtained and in a known manner, for. B. by filtering, isolated and optionally cleaned by washing with an inert organic solvent.
  • the compounds of formula (1) according to the invention and their acid addition salts have antimicrobial, in particular antifungal, effects. They have a very broad spectrum of antifungal effects, especially against dermatophytes and sprout fungi as well as biphasic fungi, e.g. B: against Candida species such as Candida albicans, Epidermophyton species such as Epidermophyton floccosum, Aspergillus species such as Aspergillus niger and Aspergillus fumigatus such as Trichophyton mentagrophytes, Microsporon species such as Microsporon felineum and Penicillium ses such as Penicillium commune. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the preparation of these preparations.
  • the present invention also includes pharmaceutical preparations in dosage units.
  • the preparations in the form of individual parts for. B. tablets, coated tablets, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose.
  • the dosage units can e.g. 1,2,3 or 4 individual doses or 1/2 1/3 or 1/4 of an individual dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
  • Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. B. glycerin, (d) disintegrant, e.g. B. agar, calcium carbonate and sodium bicarbonate, (e) solution retarders, e.g. B. paraffin and (f) absorption accelerator, e.g. B.
  • fillers and extenders e.g. B. starches, milk sugar, cane sugar, glucose, mannitol and silica
  • binders e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl
  • quaternary ammonium compounds (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate, (h) adsorbent, e.g. B. kaolin and bentonite and (i) lubricants, e.g. B. talc; Calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • wetting agents e.g. B. cetyl alcohol, glycerol monostearate
  • adsorbent e.g. B. kaolin and bentonite
  • lubricants e.g. B. talc
  • the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, where as Embedding compounds e.g. B. polymer substances and waxes can be used.
  • Embedding compounds e.g. B. polymer substances and waxes can be used.
  • the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Suppositories can contain the usual water-soluble or water-insoluble excipients in addition to the active ingredient or ingredients, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
  • B. polyethylene glycols e.g. B. polyethylene glycols
  • fats e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
  • Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • active ingredient e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual blowing agents such. B. contain chlorofluorocarbons.
  • Solutions and emulsions can in addition to the active ingredient (s) the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylene benzate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glyceryl ether, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty acid, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol, fatty alcohol of sorbitan or mixtures of these substances.
  • solvents e.g. B
  • solutions and emulsions can also be in sterile and blood isotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. B. water, ethyl alcohol, propylene glycol, suspending agents, e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. B. water, ethyl alcohol, propylene glycol
  • suspending agents e.g. B. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • the formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, e.g. B. contain saccharin.
  • the therapeutically active compounds are said to be in the pharmaceutical listed above Preparations are preferably present in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.
  • the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. B. by mixing the active ingredient (s) with the excipient (s).
  • the active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.
  • the active ingredient (s) according to the invention in total amounts of about 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to achieve the desired results.
  • the incubation temperature was 20 ° C, the incubation time was 24 to 96 hours.
  • the compounds according to the invention showed good minimal inhibitory concentrations against the fungi mentioned above.
  • mice of the type SPF-CF were infected intravenously with 1-2 x 10 6 logarithmically growing Candida cells, which were suspended in physiological saline. One hour before and seven hours after the infection, the animals were treated orally with 50-100 mg / kg body weight of the preparations.
  • MICONAZOL® 1- [2,4-dichloro- ⁇ - (2.4-dichlorobenzyloxy) phenylethyl] imidazole nitrate
  • a solution of 13.1 g (0.05 mol) of 4-biphenylyl- (imidazol-1-yl-methyl) ketone in 500 ml of benzene is converted into a 4-chlorobenzylmagnesium chloride solution, obtained from 6.1 g (0, 25 mol) magnesium and 40.2 g (0.25 mol) 4-chlorobenzyl chloride in 150 ml ether, added dropwise.
  • the ether is then distilled off and the reaction mixture is heated to 80 ° C. for about 8 hours.
  • the cooled solution is poured onto an ammonium chloride solution, the organic phase is separated off, washed with water and dried over sodium sulfate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (3)

1. Des hydroxypropyl-imidazoles de formule générale (I):
Figure imgb0029
dans laquelle:
R est un groupe phényle éventuellement substitué par un halogène ou par un radical alkyle ayant 1 à 4 atomes de carbone, un groupe naphtyle ou un groupe tétrahydronaphtyle;
R1 est un groupe phényle éventuellement substitué par un halogène ou par un radical alkyle ayant 1 à 4 atomes de carbone ou un groupe cycloalkyle ayant 5, ou 7 atomes de carbone; et
R2 est de l'hydrogène, ou
R1 et R2 forment ensemble, en position ortho l'un par rapport à l'autre, un pont triméthylénique, tétraméthylénique ou pentaméthylénique,

et leurs sels d'addition d'acides acceptables du point de vue physiologique.
2. Procédé de production d'hydroxypropyl-imidazoles de formule générale (I) suivant la revendication 1, caractérisé en ce qu'on fait réagir:
a) des imidazolyl-méthyl-phényl-cétones de formule:
Figure imgb0030
dans laquelle:
R1 et R2 ont la définition indiquée dans la revendication 1, avec un composé de Grignard de formule:
Figure imgb0031
dans laquelle:
R a la définition indiquée dans la revendication 1 et
X est un halogène, notamment le chlore ou le brome, en présence d'un diluant, ou
b) des 1-halogéno-propane-2-ols de formule:
Figure imgb0032
dans laquelle:
R, R1 et R2 ont la définition indiquée dans la revendication 1 et
Y est un halogène, notamment le chlore ou le brome,

avec l'imidazole, éventuellement en présence d'un accepteur d'acide et en la présence éventuelle d'un diluant et les composés ainsi obtenus sont alors éventuellement transformés en leurs sels.
3. Médicament, caractérisé par une teneur en au moins un hydroxypropyl-imidazole de formule générale (1) suivant la revendication 1.
EP79101288A 1978-05-10 1979-04-30 Hydroxypropyl-imidazoles, procédé pour leur préparation et médicaments les contenant Expired EP0005250B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19782820489 DE2820489A1 (de) 1978-05-10 1978-05-10 Hydroxypropyl-imidazole, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
DE2820489 1978-05-10
DE19782832677 DE2832677A1 (de) 1978-07-26 1978-07-26 Hydroxypropyl-imidazole, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
DE2832677 1978-07-26

Publications (3)

Publication Number Publication Date
EP0005250A2 EP0005250A2 (fr) 1979-11-14
EP0005250A3 EP0005250A3 (en) 1979-12-12
EP0005250B1 true EP0005250B1 (fr) 1981-08-12

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EP79101288A Expired EP0005250B1 (fr) 1978-05-10 1979-04-30 Hydroxypropyl-imidazoles, procédé pour leur préparation et médicaments les contenant

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US (1) US4246274A (fr)
EP (1) EP0005250B1 (fr)
DE (1) DE2960621D1 (fr)
ES (1) ES480426A1 (fr)
IL (1) IL57229A (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016174244A1 (fr) 2015-04-29 2016-11-03 Malteries Soufflet Utilisation de cysteine endoprotéase pour diminuer le trouble de boissons

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US4277486A (en) * 1979-03-09 1981-07-07 Syntex (U.S.A.) Inc. 1-[(Substituted-naphthyl)ethyl]-imidazole derivatives
DE2920375A1 (de) * 1979-05-19 1980-11-20 Bayer Ag Fungizide mittel, verfahren zu ihrer herstellung sowie ihre verwendung als fungizide
AU542623B2 (en) * 1980-05-16 1985-02-28 Bayer Aktiengesellschaft 1-hydroxyethyl-azole derivatives
DE3018865A1 (de) * 1980-05-16 1981-11-26 Bayer Ag, 5090 Leverkusen Antimikrobielle mittel
US5006513A (en) * 1987-11-09 1991-04-09 Miles Inc. Antimycotic compositions of nikkomycin compounds and azole antimycotica
US5194427A (en) * 1987-11-09 1993-03-16 Bayer Ag Antimycotic compositions of nikkomycin compounds and azole antimycotics
US5096889A (en) * 1987-11-09 1992-03-17 Bayer Ag Antimycotic compositions of nikkomycin compounds and azole antimycotics
US4914087A (en) * 1988-02-29 1990-04-03 Bayer Ag Nikkomycin derivatives, antimycotic compositions of nikkomycin derivatives and azole antimycotics
SG11202002032SA (en) 2017-09-22 2020-04-29 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
IL272667B (en) 2017-10-18 2022-09-01 Jubilant Epipad LLC Imidazo-pyridine compounds as pad inhibitors
SG11202004143XA (en) 2017-11-06 2020-06-29 Jubilant Prodel LLC Pyrimidine derivatives as inhibitors of pd1/pd-l1 activation
WO2019102494A1 (fr) 2017-11-24 2019-05-31 Jubilant Biosys Limited Composés hétérocycliques utilisés en tant qu'inhibiteurs de prmt5
CN112105610B (zh) 2018-03-13 2024-01-26 朱比连特普罗德尔有限责任公司 作为pd1/pd-l1相互作用/活化的抑制剂的双环化合物

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Publication number Priority date Publication date Assignee Title
DE2213863C3 (de) * 1972-03-22 1982-05-13 Bayer Ag, 5090 Leverkusen Disubstituierte Triphenylmethylimidazole, Verfahren zu ihrer Herstellung sowie diese enthaltende Arzneimittel
DE2333354C2 (de) * 1973-06-30 1983-12-15 Bayer Ag, 5090 Leverkusen 2-Aryloxy-2-(imidazol-1-yl)-äthanole sowie deren Salze, Verfahren zu ihrer Herstellung und ihre Verwendung als Fungizide
DE2350123C2 (de) * 1973-10-05 1983-04-14 Bayer Ag, 5090 Leverkusen 1-Propyl-imidazol-Derivate und deren Salze, Verfahren zu ihrer Herstellung und ihre Verwendung als Fungizide
US4101664A (en) * 1975-10-06 1978-07-18 Janssen Pharmaceutica N.V. 1-(2-Ar-4-aryloxymethyl-1,3-dioxolan-2-ylmethyl)-imidazoles
DE2623129C3 (de) * 1976-05-22 1980-04-10 Nordmark-Werke Gmbh, 2000 Hamburg U-Diphenyl-3-(imidazol-l-yl) -propan-2-ole, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel
DE2705676A1 (de) * 1977-02-11 1978-08-17 Bayer Ag Fungizide mittel
DE2732750A1 (de) * 1977-07-20 1979-02-08 Merck Patent Gmbh Basische thioaether und verfahren zu ihrer herstellung
DE2736122A1 (de) * 1977-08-11 1979-02-22 Basf Ag Fungizide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016174244A1 (fr) 2015-04-29 2016-11-03 Malteries Soufflet Utilisation de cysteine endoprotéase pour diminuer le trouble de boissons

Also Published As

Publication number Publication date
IL57229A (en) 1982-08-31
US4246274A (en) 1981-01-20
EP0005250A2 (fr) 1979-11-14
DE2960621D1 (en) 1981-11-12
ES480426A1 (es) 1979-12-01
IL57229A0 (en) 1979-09-30
EP0005250A3 (en) 1979-12-12

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